Halo-sulfamylspiro- and dialkyl-quinazolinones

ABSTRACT

A 7&#39;&#39;HALO-6&#39;&#39;-SULFAMYLSPIRO- OR DIALKYL-4,2&#39;&#39;(1&#39;&#39;H)-QUINAZOLIN-4&#39;&#39;(3&#39;&#39;H)-ONE, HAVING THE SPIRO GROUP IN THE 2-POSITION, HYDROGEN OR ALKYL IN THE 3-POSITION, AND HYDROGEN, ALKYL, AMINO, HALOGEN OR HALOLOWERALKYL IN THE 5- AND 8-POSITIONS. THE HYDROGENS OF THE SULFAMYL GROUP MAY BE SUBSTITUED BY ALKYL OR PHENYLALKYL OR TOGERTHER FORM A CARBOCYCLIC OR HETEROCYCLIC RING. THE SPIRO GROUP CAN BE COMPOSED ENTIRELY OF CARBON ATOMS OR CAN CONTAIN ONE OR MORE HETERO ATOMS, ESPECIALLY SULFUR, NITROGEN OR OXYGEN. THE COMPOUNDS ARE USEFUL IN DIURETICS AND SALURETICS.

United States Patent No Drawing.

11 Claims R and R are hydrogen, loweralkyl, loweralkoxy, amino,

logelralkylarnino, halogen or halogen substituted lowera y X is halogen or trifiuoromethyl;

R is hydrogen, loweralkyl or phenyllowei'alkyl;

R is hydrogen or loweralkyl, or

R and R together form a carbocyclic ring such as cyclopropyl, cyclobutyl, or a heterocyclic ring such as piperidino, morpholino, pyrolidino;

R is hydrogen, lower alkyl, or phenylloweralkyl.

'ice

ABSTRACT OF THE DISCLOSURE Th f H l H t d f h A7'halo-6-sulfamylspii'oor dialkyl-4,2'(1H)quinazog f eXamP es 1 rate 5 e lin-4'(3'H)-one, having the spiro group in the 2-position, l or alkyl m the and hydrogen filkyl, 7'-chloro-1-methyl-6'-methylaminosulfony1-3-o-to1ylamino, halogen or haloloweralkyl in the 5- and 8-posi tions. Spiro [PiPeridineAZT1'H) quinaZ01in] 4,(3,H) one The hydrogens of the sulfamyl group may be substitu 7 -chloro-1,1'-dimethyl-6-sulfamylspiro [piperidine-4,2' by alkyl or phenylalkyl or together form a carbocyclic or 1 heterocyclic ring. The spiro group can be compose 7-chloro-1-methy1-6'-methy1aminosulfonylspiro [piperitirely of carbon atoms or can contain one or more hetero dine 472,(1,H) quinaZo1in] atoms especlally {Imogen or F The 7-chloro-6'-methylaminosulfonylspiro [cyclopentane-1,2' pounds are useful in diuretics and saluretics. (1,H) quinaZo1in] 4,(3,H) one.

2,2-dimethy1-6-su1famyl-7-chloro-1,2,3,4-tetrahydro- 4(3H)-quinazo1inone. The invention relates to spiro or dialkyl quinazolinorie 2 ethy1 2 methy1 6 sulfamyl 7 chloro 12,3,4 tetrahydro compounds having diuretic properties, and more parhc- 4(3H) quinazolinone ularly to 7'ha1o or 7'trifiuoromethyl-6'-sulfamyl (substi- 7 chloro 6, sulfamylspiro [cyc1opentane 1,2,(1,H) tuted or unsubstituted) sp ro 4,2( 1H) quinagolin-4 quinaZo1in] 4,(3,H) 0ne (3'H) ones having the spiro group n the 2-position. 7, chloro 6, sulfamylspiro [Cyc1oheXane 1,2,(1,H)

The preferred compounds of the invention are of the quinazoun] 4,(3,fi) one following general formula: 7-chloro-1-methyl-6-su1fainy1spiro [piperidine-4,2'

(1H)-quinazolii1]-4'(3H)-one.

)5 2-methyl-2-chloromethy1-6-sulfamyl-7-chloro-1,2,3,4- X tetrahydro-4(3H)-quinazolinone. S 2,2-dimethyl-6-su1famy1-7-trifiuoromethyl-1,2,3,4-tetra- 2 \C/ hydro-4(3H)-quinazolinone.

t 2-carbethoxyinethyl-2-methyl-6-sulfamyl-7-chloro-1,2,31,4-

. tetrahydro-4 3H -quinazolinone. R and R are loweralkyl or together form With the 2- carbon atom to which they are attached, a spiro-ali- 40 ii chloro phatic group that can be composed entirely of carbon )qmmfzo I atoms or can contain one or more hetero atoms especial- 4,7 -4 'lsulfamylsplm [cyclohexaneiz ly sulfur, nitrogen or oxygen, and can be substituted or qulnazollnl'4 unsubstituted, especially alkyl or halo substituted; the hl r 2 methyl-o u a y Piro [cyclohcxanecarbocyclic or heterocyclic group containing preferably )-q not more than 10 carbon atoms; The following table gives compounds which also illus- R is hydrogen, or loweralkyl; trate the diuretic compounds of this invention:

Me=methyl Et=ethyl Ph=phenyl R1 R2 Rz Ra X R5 R4 R5 R H O H H Cl H H H Me I Cl H Q H H Cl H H H II H c H H C] H H H H H Q Me H 01 H H H H H H G1 H H H H The following examples are given to illustrate the preparation of compounds of this invention. Other compounds of this invention than those specifically shown can be pre- Preparation of 5-chloro-Z-methylacetanilide, II

S-chloro-o-toluidine (I), (1000 gm.) was added to 9000 m1. of water, preheated to in a 4 /2 gallon battery jar. The slurry was vigorously stirred while 1260 gm. acetic anhydride was carefully added. Stirring was continued for four hours, then the product was filtered off and air dried. The crude product was recrystallized from 7500 ml. of benzene, using gm. charcoal to remove some colored material. The product was air dried. It weighed 818 gm. and melted at 138-139". This lot was combined with the material from lot numbers, 741-811, 741-859, 741-874, 745-612, 741-994, and 740-482. The total weight was 11 kg. from 10.4 kg. of starting material.

Preparation of 5-chloro-2-methyl-4-sulfamylacetanilide, III

Chlorosulfonic acid (1000 gm.) was placed in 9. nitrogen flushed 5 liter, 3 neck round bottom flask fitted with a stirrer and a calcium chloride tube. 5-chloro-2-methylacetanilide (300 gm.) was cautiously added to the chlorosulfonic acid, and then 88 gm. sodium chloride was added portionwise over one hour. The reaction mixture was cautiously raised to C. (foaming occurs). When the foaming had subsided, the temperature was raised to 92 C. and held there for three hours. The hot reaction mixture was added slowly with good agitation to 4000 ml. of acetone and 1500 gm. of ice. The resulting slurry was diluted with water to a total volume of 8000 ml. and the crude sulfonyl chloride was filtered off and washed with water. The damp filter cake was added to 3000 ml. of concentrated ammonium hydroxide, stirred at room temperature for one hour and then heated to 50 C. for two hours. The slurry was cooled, filtered, washed with water and air dried. The weight of product was 186 gm. It melted at 248-250. This material was combined with that made in runs 741-863, 741-886, 747-505, 747-507, 747-903, and 745-647. The total weight of product was 4 kg. from 11 kg. starting material.

Preparation of N-acetyl-4-chloro-S-sulfamyl anthranilic acid, IV

Into a 12 liter flask was introduced 8000 ml. water, 1144 gm. magnesium sulfate heptahydrate and 400 gm. 5 chloro 2 methyl 4 sulfamylacetanilide. The mixture was heated to 80 and 710 gm. potassium permanganate was added portionwise with good stirring over about four hours at 8085. The mixture was kept at 80-85. for three hours after the permanganate addition was completed and then it was filtered hot. The manganese dioxide cake was washed with three 1000 ml. portions of water.

The filtrate was made acid with 200 ml. concentrated hydrochloric acid, filtered, washed with water and air dried. The crude product was combined with the crude product obtained from runs 743-858, 747-552, 742-237, 745-685, 747-529, and 740-245, giving a total weight of 2833 gm. This material was dissolved, (under Lot No. 745-687) in 100 liters of 95% ethanol. The resulting solution was concentrated to a total volume of 10 liters, periodically filtering off the product that had crystallized out and washing this with 95% ethanol. The yield of purified product was 2500 gm. melting at 264-266", from 3 kg. of starting material.

Preparation of 4-chloro-5-sulfamylanthranilic acid, V

N acetyl 4 chloro-S-sulfamylanthranilic acid (2500 gm.) was refluxed for three hours in 15,000 ml. 3 N sodium hydroxide solution, then brought to a pH of four with concentrated hydrochloric acid. After allowing it to cool to about 70, the product was filtered off and washed with water. The wet product was dissolved in 200 liters of boiling water, filtered hot and allowed to cool. When filtered, washed with water and air dried, the product weighed 2000 gm. and melted at 275-276.

Preparation of methyl-4-chloro-S-sulfamylanthranilate, VI

4-chloro-5-sulfamylanthranilic acid (200 gm.) was refluxed 24 hours in 2 liters methanol and ml, concentrated sulfuric acid. It was cooled and the mixture used in the next step without further purification.

Preparation of 2-amino-4-chloro-5-sulfamyl- 'benzamide, VII

The slurry of methyl-4-chloro-S-sulfamylanthranilate was added to 7 liters of concentrated NH OH and stirred for 7 days. The reaction mixture was filtered, concentrated on the rotovap to 4 liters and the solid filtered, washed with 400, 200 and 200 ml. portions of water, then with ether. The product was dried in vacuo over P 0 to give 86% of the product. M.P.=277-9 (dec.).

Preparation of 7-chloro-6'-sulfamylspiro [cyclopentane- 1,2(1'H)-quinazolin]-4(3 'H) -one, VIII To a suspension of 10 gm. 2-amino-4-chloro-5-sulfamylbenzamide in 100 m1. acetic acid was added 4.1 ml. cyclopentanone and 14 drops of concentrated sulfuric acid. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with acetic EXIXMPLE 2 Preparation of 7-chloro-1-methyl-6-sulfamylspiro [piperidine-4,2-(1H)-quinazolin]-4(3H)-one sulfate VIII Synthetic route:

Preparation of -chloro-Z-methylacetanilide, II

S-chloro-o-toluidine (I), (1000) gm.) was added to 9000 ml. of water, preheated to 35, in a 4%. gallon battery jar. The slurry was vigorously stirred while 1260 gm. acetic anhydridew as carefully added. Stirring was continued for four hours, then the product was filtered 011 and air dried. The crude product was recrystallized from 7500 ml. of benzene, using 40 gm. charcoal to remove some colored material. The product was air dried. It weighed 818 gm. and melted at 138-139. This lot was combined with the material from lot numbers, 741-811, 741-859, 741-874, 745-612, 741-994, and 740-482. The total weight was 11 kg. from 10.4 kg. of starting material.

Preparation of 5-chloro-2-methyl-4- sulfamylacetanilide, III

Chlorosulfonic acid (1000 gm.) was placed in a nitrogen fiushed 5 filter, 3 neck round bottom flask fitted with a stirrer anda calcium chloride tube. 5-chloro-2-methylacetanilide (300 gm.) was cautiously added to the chlorosulfonic acid, and then 88 gm. sodium chloride was added portionwise over one hour. The reaction mixture was cautiously raised to C. (foaming occurs). When the foaming had subsided, the temperature was raised to 92 C. and held there for three hours. The hot reaction mixture was added slowly with good agitation to 4000 ml. of acetone and 1500 gm. of ice. The resulting slurry was diluted with water to a total volume of 8000 ml. and the crude sulfonyl chloride was filtered 01? and washed with water. The damp filter cake was added to 3000 ml. of concentrated ammonium hydroxide, stirred at room temperature for one hour and then heated to 50 C. for two hours. The slurry was cooled, filtered, washed with water and air dried. The Weight of product was 186 gm. It melted at 248-250. This material was combined with that made in runs 741-863, 741-886, 747-505, 747-507, 747-903, and 745-647. The total weight of product was 5 kg. from 11 kg. starting material.

Preparation of N-acetyl-4-chloro-5-sulfamyl anthranilic acid, IV

Into a 12 liter flask was introduced 8000 ml. water, 1144 gm. magnesium sulfate heptahydrate and 400 gm. 5-chloro-2-methyl-4-sulfamylacetanilide. The mixture was heated to 80 and 710 gm. potassium permanganate was added portionwise with good stirring over about four hours at 80-85. The mixture was kept at 80-85 for three hours after the permanganate addition was completed and then it was filtered hot. The manganese dioxide cake was washed with three 1000 ml. portions of water.

The filtrate was made acid with 200 ml. concentrated hydrochloric acid, filtered, washed with water and air dried. The crude product was combined with the crude product obtained from runs 743-858, 747-552, 742-237, 745-685, 747-529, and 740-245, giving a total weight of 2833 gm. This material was dissolved, (under Lot No. 745-687) in 100 liters of 95% ethanol. The resulting solution was concentrated to a total volume of 10 liters, periodically filtering oh the product that had crystallized out and washing this with 95% ethanol, The yield of purified product was 2500 gm. melting at 264-266 (from 3 kg. of starting material).

Preparation of 4-chloro-5-sulfamylanthranilic acid, V

N-acetyl 4 chloro 5 sulfamylanthranilic acid 25 00 gm.) was refluxed for three hours in 15,000 ml. 3 N sodium hydroxide solution, then brought to a pH of four with concentrated hydrochloric acid. After allowing it to cool to about 70, the product was filtered off and washed with water. The wet product was dissolved in 200 liters of boiling water, filtered hot and allowed to cool. When filtered, washed with water and air dried, the product weighed 2000 gm. and melted at 275-276 Preparation of methyl-4-chloro-5- sulfamylanthranilate, VI

4-chloro-5-sulfamylanthranilic acid (200 gm.) was refluxed 24 hours in 2 liters methanol and ml. concentrated sulfuric acid. It was cooled and the mixture used in the next step without further purification.

Preparation of 2-amino-4-chloro-5- sulfamylbenzamide, VII

The slurry of Inethyl-4-chloro-5-sulfamylanthranilate Was added to 7 liters of concentrated NH OH and stirred for 7 days. The reaction mixture was filtered, concentrated on the rotovap to 4 liters and the solid filtered, washed with 400, 200 and 200 ml. portions of water, then with ether. The product was dried in vacuo over P 0 to give 86 gm. of the product. M.P.=277-9 (dec.).

Preparation of 7' chloro 1 methyl 6 sulfamyl-spiro [piperidine-4,2(1H)-quinazolin]4(3'H)-one sulfate, VIII EXAMPLE 3 Preparation of 2,2-dimethyl 6-sulfamyl-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone Synthetic route:

Cl NH; (CHQCOMO Cl NHCO CH 1. CISOSH CH3 2. NH

Cl NHCOCH; [O]

(KMnO4) III 01- NHCOCH3 9 112N028 -o 0 on A Cl- NH;

MeOH

H NO S- coon H25 04 HgNO S OOO CH H ON N 3 C CHa I'm Cl NH2 Cl- VII VIII Preparation of -chloro-2-methylacetanilide, II

5-chloro-o-toluidine (I), (1000 gm.) was added to 9000 ml. of water, preheated to 35, in a 4 /2 gallon battery jar. The slurry was vigorously stirred while 1260 gm. acetic anhydride Was carefully added. Stirring was continued for four hours, then the product was filtered off and air dried. The crude product was recrystallized from 7500 ml. of benzene, using 40 gm. charcoal to remove some colored material. The product was air dried. It weighed 818 gm. and melted at 138-139. This lot was combined with the material from lot numbers, 741-811, 741-859, 741-874, 745-612, 741-994, and 740-482. The total weight Was 11 kg. from 10.4 kg. of starting material.

Preparation of 5-chloro-2-methyl- 4-sulfamylacetanilide, II-I Chlorosulfonic acid (1000 gm.) was placed in a nitrogen flushed 5 liter, 3 neck round bottom flask fitted with a stirrer and a calcium chloride tube. 5-chloro-2-methylacetanilide (300 gm.) was cautiously added to the chlorosulfonic acid, and then 88 gm. sodium chloride was added portionwise over one hour. The reaction mixture was cautiously raised to C. (foaming occurs). When the foaming had subsided, the temperature Was raised to 92 C. and held there for three hours. The hot reaction mixture was added slowly with good agitation to 4000' ml. of acetone and 1500 gm. of ice. The resulting slurry was diluted with water to a total volume of 8000 ml. and the crude sulfonyl chloride was filtered off and washed with water. The damp filter cake was added to 3000 ml. of concentrated ammonium hydroxide, stirred at room temperature for one hour and then heated to 50 C. for two hours. The slurry was cooled, filtered, washed with water and air dried. The weight of product was 186 gm. It melted at 248-250. This material was combined with that made in runs 741-863, 741-886, 747-505, 747-507, 747-903, and 745-647. The total weight of product was 4 kg. from 11 kg. starting material.

Preparation of N-acetyl-4-chloro- 5-sulfamyl anthranilic acid, IV

Into a 12 liter flask was introduced 8000 ml. water, 1144 gm. magnesium sulfate heptahydrate and 400 gm. 5-chloro-2-methyl-4-sulfamylacetanilide. The mixture was heated to 80 and 710 gm. potassium permanganate was added portionwise with good stirring over about four hours at 80-85. The mixture was kept at 80-85" ,for three hours after the permanganate addition was completed and then it was filtered hot. The manganese dioxide cake was washed with three 1000 ml. portions of water.

The filtrate was made acid with 200 ml. concentrated hydrochloric acid, filtered, Washed with water and air dried. The crude product was combined with the crude product obtained from runs 743-858, 747-552, 742-237, 745-685, 747-529, and 740-245, giving a total weight of 2833 gm. This material was dissolved, under Lot #745- 687) in 100 liters of 95 ethanol. The resulting filtering off the product that had crystallized out and washing this with 95% ethanol. The yield of purified product was 2500 gm. melting at 264-266", from 3 kg. of starting material.

Preparation of 4-chloro-5-sulfamylanthranilic acid, V

N-acetyl-4-chloro-S-suIfamylanthranilic acid (2500 gm.) was refluxed for three hours in 15,000 ml. 3 N sodium hydroxide solution, then brought to a pH of four with concentrated hydrochloric acid. After allowing it to cool to about 70, the product was filtered off and washed with water. The wet product was dissolved in 200 liters of boiling water, filtered hot and allowed to cool. When filtered, washed with water and air dried, the product weighed 200:0 gin. and melted at 275-276 Preparation of methyl-4-chloro-5-sulfamylanthranilate, VI

4-chloro-5-sulfamylanthranilic acid (200 gm.) was refluxed 24 hours in '2 liters methanol and ml. concentrated sulfuric acid. It was cooled and the resulting mixture Was used in the next step without further purification.

Preparation of 2-amino-4-chloro- 5-sulfamylbenzamide, VII

The slurry of methyl-4-chloro-5-sulfamylanthranilate was added to 7 liters of concentrated NH OH and stirred for 7 days. The reaction mixture was filtered, concentrated on the rotovap to 4 liters and the solid filtered, washed with 400, 200 and 200 ml. portions of water, then with ether. The product was dried in vacuo over P 0 to give 86 gm. of the product. M.P.'=277-9 (dec.).

Preparation of 2,2-dimethyl-6-sulfamyl-7-chloro- 1,2,3,4-tetrahydro-4-quinazolinone, VIII 2-amino-4-chloro-5-sulfamylbenzamide (10 gm.), acetone (10 ml.) and acetic acid (50 ml.) were stirred vigorously at room temperature and 5 drops of concentrated sulfuric acid added. After 1 hour, the solid was filtered, washed with acetic acid, then with ether and dried in vacuo at for 3 hours. The product was dissolved in 20 ml. dimethylformanide, filtered, and 2-0 ml. hot water 11 added to give 8.0 gm. of the product. M.P. =305-20 (dec.).

Calc. (percent): C, 41.45; H, 4.18; Cl, 12.24; N, 14.50; S, 11.07. Found (percent): 41.28; H, 4.17; Cl, 12.21, 12.36; N, 14.63; S, 11.09.

EXAMPLE 4 Preparation of 2-chloromethyl-2-methyl-6-sulfamyl-7- chloro-1,2,3,4-tetrahydro-4-quinazolinone Synthetic route:

HE? (orraoono "181100919 1. ClCOaH 2 NH -0H --CH 3 3 I II 01 -rsncoorr, [O]

l HzNozs ammo.)

or \-NHCOCH; 9 l HgNOgS -COOH A 01 NH2 MeOI-I Nrriorr mnozs -o0o11 H280 HzNOzS -cooorr,

V VI

I C1 N112 womb-0H3 mnogs CONH2 vrr on, N (ID- CH2Cl NH 2 0Zs II 0 VIII Preparation of -chloro-2-methylacetanilide, II

S-chloro-o-toluidine (I), (1000 gm.) was added to 9000 ml. of water, preheated to in a 4 /2 gallon battery jar. The slurry was vigorously stirred while 1260 gm. acetic anhydride was carefully added. Stirring was continued for four hours, then the product was filtered off and air dried. The crude product was recrystallized from 7500 ml. of benzene, using gm. charcoal to remove some colored material. The product was air dried. It weighed 818 gm. and melted at 138139. This lot was combined with the material from lot numbers, 741-811, 741-859, 741-874, 745-612, 741-994, and 740-482. The total weight was 11 kg. from 10.4 kg. of starting material.

Preparation of 5-chloro-2-methyl-4-sulfamylacetanilide, III

Chlorosulfonic acid (1000 gm.) was placed in a nitrogen flushed 5 liter, 3 neck round bottom fiask fitted with a stirrer and a calcium chloride tube. 5-chloro-2-methylacetanilide (300 gm.) was cautiously added to the chlorosulfonic acid, and then 88 gm. sodium chloride was added portionwise over one hour. The reaction mixture was cautiously raised to 80 C. (foaming occurs). When the foaming had subsided, the temperature was raised to 92 C. and held there for three hours. The hot reaction mixture was added slowly with good agitation to 4000 ml. of acetone and 1500 gm. of ice. The resulting slurry was di- 12 luted with water to a total volume of 8000 ml. and the crude sulfonyl chloride was filtered off and washed with water. The clamp filter cake was added to 3000 ml. of concentrated ammonium hydroxide, stirred at room temperature for one hour and then heated to 50 C. for two hours. The slurry was cooled, filtered, washed with water and air dried. The weight of product was 186 gm. It melted at 248250. This material was combined with that made in runs 741-863, 741-886, 747-505, 747-507, 747-903, and 745-647. The total weight of product was 4 kg. from 11 kg. starting material.

Preparation of N-acetyl-4-chloro-S-sulfamyl 'anthranilic acid, IV

Into a 12 liter flask was introduced 8000 ml. water, 1144 gm. magnesium sulfate heptahydrate and 400 gm. 5-chloro-2-rnethyl-4-sulfamylacetanilide. The mixture was heated to and 710 gm. potassium permanganate was added portionwise with good stirring over about four hours at 80-85". The mixture was kept at 8085 for three hours after the permanganate addition was completed and then it was filtered hot. The manganese dioxide cake was washed with three 1000 ml. portions of water.

The filtrate was made acid with 200 ml. concentrated hydrochloric acid, filtered, washed with water and air dried. The crude product was combined with the crude product obtained from runs 743-858, 747-552, 742-237, 745-685, 747-529, and 740-245, giving a total weight of 2833 gm. This material Was dissolved, (under Lot No. 745-687) in 100 liters of ethanol. The resulting solution was concentrated to a total volume of 10 liters, periodically filtering off the product that had crystallized out and washing this with 95% ethanol. The yield of purified product was 2500 gm. melting at 264-266, from 3 kg. of starting material.

Preparation of 4-chloro-5-sulfamylanthranicil acid, V

N acetyl 4-chloro-5-sulfamylanthranilic acid (2500 gm.) was refluxed for three hours in 15,000 ml. 3 N sodium hydroxide solution, then brought to a pH of four with concentrated hydrochloric acid. After allowing it to cool to about 70, the product was filtered off and washed with water. The wet product was dissolved in 200 liters of boiling water, filtered hot and allowed to cool. When filtered, washed with water and air dried, the product weighed 2000 gm. and melted at 275-276.

Preparation of methyl-4-chloro-5-sulfamylanthranilate, VI

4-chloro-S-sulfamylanthranilic acid (200 gm.) was refluxed 24 hours in 2 liters methanol and ml. concentrated sulfuric acid. It was cooled and the mixture used in the next step without further purification.

Preparation of 2-amino-4-chloro-5-sulfamylbenzamide, VII

The slurry of methyl-4-chloro-5-sulfamylanthranilate was added to 7 liters of concentrated NH OH and stirred for 7 days. The reaction mixture was filtered, concentrated on the rotovap to 4 liters and the solid filtered, washed with 400, 200 and 200 ml. portions of water, then with ether. The product was dried in vacuo over P 0 to give 86 gm. M.P.=277-9 (dec.).

Preparation of 2-chloromethyl-2-methyl-6-sulfamyl-7- chloro-l,2,3,4-tetrahydro-4-quinazolinone, VIII 2-amino-4-chloro-S-suIfamylbenzamide (10 gm.), chloro-2-propanone (10 ml.), acetic acid (50 ml.) and concentrated sulfuric acid (6 drops) were heated to 118 over 15 minutes. The temperature maintained for 5 minutes, the mixture cooled and filtered after 1 hour to give 14 gm. product which was dried 5 hours at 100 to give 11.9 gm. M.P.=248-52.

Calc. (percent) C, 37.05; H, 3.42; CI, 21.88; N, 12.97; S, 9.90. Found (percent): C, 37.02; H, 3.41; Cl, 21.96, 22.01; N, 12.78; S, 9.99.

13 EXAMPLE Preparation of 7'-chloro-6-sulfamylspiro [cyclohexano- 1,2' 1"H) -quinazolin] -4 (3 'H) -one Synthetic route:

NHCOCH 1. ClSOzH Preparation of 5-chloro-2-methylacetanilide, II

S-chloro o-toluidine (I), (1000 g'm.) was added to 9000 ml. of water, preheated to 35, in a 4 /2 gallon batter jar. The slurry was vigorously stirred while 1260 gm. acetic anhydride was carefully added. Stirring was continued for four hours, then the product was filtered off and air dried. The crude product was recrystallized from 7500 ml. of benzene, using 40 gm. charcoal to remove some colored material. The product was air dried. It weighed 818 gm. and melted at 138-13'9. This lot was combined with the material from lot numbers, 741- 811, 741-859, 741-874, 745-612, 741,994, and 740-482. The total weight was 11 kg. from 10.4 kg. of starting material.

Preparation of 5-chloro-2-methyl-4-sulfamylacetanilide, III

Chlorosu'lfonic acid (1000 gm.) was placed in a nitrogen fiushed 5 liter, 3 neck round bottom flask fitted with a stirrer and a calcium chloride tube. S-chloro-Z-methylacetanilide (300 gm.) was cautiously added to the chlorosulfonic acid, and then 88 gm. sodium chloride was added portionwise over one hour. The reaction mixture was cautiously raised to 80 C. (foaming occurs). When the foaming had subsided, the temperature was raised to 92 C. and held there for three hours. The hot reaction mixture was added slowly with good agitation to 4000* ml. of acetone and 1500 gm. of ice. The resulting slurry was diluted with water to a total volume of 8000 ml. and the crude sulfonyl chloride was filtered off and washed with water. The damp filter cake was added to 3000 ml. of concentrated ammonium hydroxide, stirred at room temperature for one hour and then heated to 50 C. for two hours. The slurry was cooled, filtered, washed with water and air dried. The weight of product was 186 gm. It melted at 248-250. This material was combined with that made in runs 741-863, 741-886, 747-505, 747-507,

14 747-903, and 745-647. The total weight of product was 4 kg. from 11 kg. starting material.

Preparation of N-acetyl-4-chloro-5-sulfamyl anthranilic acid, IV

- Into a '12 liter flask was introduced 8000 ml. water, -1 144 gm. magnesium sulfate heptahydrate and 400 gm. 5-chlor0-2-methy1-4-sulfamylacetanilide. The mixture was heated to and 710 gm. potassium permanganate was added portionwise with good stirring over about four hours at 80-85". The mixture was kept at 80-85 for three hours after the permanganate addition was completed and then it was filtered hot. The manganese dioxide cake was washed with three 1000 ml. portions of water.

The filtrate was made acid with 200 m1. concentrated hydrochloric acid, filtered, washed with water and air dried. The crude product was combined with the crude product obtained from runs 743-858, 747-552, 742-237, 745-685, 747-529, and 740-245, giving a total weight of .2833 gm. This material was dissolved, (under Lot #745- 687) in 100 liters of ethanol. The resulting solution was concentrated to a total volume of 10 liters, periodically filtering off the product that had crystallized out and washing this with 95% ethanol. The yield of purified product was 2500 gm. melting at 264266, from 3 kg. of starting material.

Preparation of 4-chloro-5-sulfamylanthranilic acid, V

/ N acetyl 4 chloro-5-sulfamylanthranilic acid (2500 gm.) was refluxed for three hours in 15,000 ml. 3 N sodium hydroxide solution, then brought to a pH of four with concentrated hydrochloric acid. After allowing it to cool to about 70, the product was filtered 01f and washed with water. The wet product was dissolved in 200 liters of boiling water and air dried, the product Weighed 2000 gm. and melted at 275276.

Preparation of methyl-4-chloro-5-sulfamylanthranilate, iVI

4-chlor-o-S-sulfamylanthranilic acid (200 gm.) was refiuxed 24 hours in 2 liters methanol and ml. concentrated sulfuric acid. The mixture was cooled and the mixture used in the next step without further purification.

Preparation of 2-amino-4-chloro-S-sulfamylbenzamide, VII

The slurry of methyl-4-chloro-5-sulfamylanthranilate was added to 7 liters of concentrated NH OH and stirred for 7 days. The reaction mixture Was filtered, concentrated on the rotovap to 4 liters and the solid filtered, washed with 400, 200, and 200 ml. portions of water, then with ether. The product was dried over P 0 to give 86 gm., M.P. 277-9 (dec.).

Preparation of 7'-chloro 6'-sulfamyl-spiro [cyclohexane- 1,2(1H)-quinazolin]-4'-(3'H)-one, VIII 2-amino-4-chloro-5-sulfamylbenzamide (10 gm.) and 6 m1. cyclohexanone were added to 100 ml. glacial acetic acid. Four drops of concentrated sulfuric acid were added, the mixture stirred 1% hours and the solid filtered, washed with acetic, then with ether and dried over P 0 under rvacuum. The solid was recrystallized from ml. 95% ethanol to give 4.3 gm., M.P. 270-4.

Calcd. (percent): C, 47.35; H, 4.89; C1, 10.75; N, 12.74. Found (percent) C, 47.11; H, 4.80; Cl, 10.79; N, 13.03.

The other compounds of this invention can be made by modification of ingredients and quantities of the above example as is well understood by those skilled in the art.

From pharmacology tests and other indications and analogy applicant states that the compounds of this invention are effective diuretics, saluretics, and antihypertensives with low toxicity. For example, the following is a summary of the pharmacology on 7'-chloro-6'-sulfamylspiro [cyclopentane- 1,2 l'H -quinazolin] -4' (3 'H) one.

15 SUMMARY (a) Symptomatology and acute LD in mice Orally: LD 1000 mg./kg. (48 hours) no symptoms at 1000 mg./kg.

Interperitoneal: LD 316 mg./kg. (48 hours) some hypothermia and decreased spontaneous motor activity at 316 mg./kg.

(b) Cardiovascular in dog Doses intravenously up to mg./kg. were administered.

There were no changes in the cardiovascular system.

(c) Diuretic assay in rats When administered by the oral route is initial assays measuring output of urine (ml./kg., Na+, and Cl (rneq./ kg.) at 4 hours and 21 hours after drug administration the said compound was found to promote water and salt loss, has a rapid onset and prolonged action, and appears to have a potency on volume diuresis better than that of quinethazone.

In the preceding specification the temperatures, wherever given, are in degrees centigrade.

Various modifications of the structural formula on page 1 of the specification may be made, such as, for example, has been done for other tetrahydro-7-halo-6-sulfamyl-4- quinazolinones known to the art, without departing from the spirit of the invention which is concerned particularly with the spiro group on the 2-position. However, the CH-substituted groups in the 2-position also have diuretic and saluretic properties when the groups in the other positions are as indicated in the general structural formula, R' being preferably hydrogen, loweralkyl, halogen substituted loweralkyl, phenyl, phenylloweralkyl, and R being one of said groups of R' except hydrogen.

Likewise, therapeutically efiective salts of the compounds of the invention may be made by methods known to the art, and are useful diuretics. For example, the sulfamyl group will react with bases to give sodium, potassium or ammonium salts of the quinazolinone compound. The basic nitrogen of the quinazolinone can be reacted with acids such as hydrochloric, maleic, tartaric, and the acidic ion exchange resins such as carboxylic acid, phosphonic acid, and sulfonic acid cation exchange resins to give the therapeutically effective and nontoxic salts of the quinazolinone compound.

or pharmaceutically acceptable salts thereof, wherein R and R together are C -C polymethylene, 3-azapentamethylene, 2-azatetramethylene, or the latter radicals optionally N-substituted with a methyl or phenyl; R is hydrogen or lower alkyl; R and R are hydrogen, lower alkyl, loweralkoxy, amino, loweralkylamino, halogen or haloloweralkyl, or phenylloweralkyl; X is halogen or trifiuoromethyl; R is hydrogen, lower alkyl or phenylloweralkyl; R is hydrogen, or loweralkyl or R and R together with the nitrogen are morpholino, piperidino or pyrrolidino.

2. A compound according to claim 1 wherein R and R' together are tetramethylene.

3. A compound according to claim 1 wherein R and R are 3 azepentamethylene.

4. A compound according to claim 1 in which the compound is 7-chl0ro-1-rnethyl-6'-methylaminosulfonyl-3'-otolylspiro-[piperidine-4,2'( lH)-quinazolin]4(3H) one.

5. A compound according to claim 1 in which the compound is 7'-chloro-1-methyl-6-methylaminosulfonylspiro [piperidine-4,2'(1H)-quinazolin]4(3H)-one.

6. A compound according to claim 1 in which the compound is 7 chloro-6'-methylaminosulfonylspiro [cyclopentane-l,2 lH)-quinazolin] -4'(3'H) -one.

7. A compound according to claim 1 in which the compound is 7' chloro-6-sulfamylspiro [cyclopentane-l,2' (1'H)-quinazolin]-4'(3H) -0ne.

8. A compound according to claim 1 in which the compound is 7-chloro 6 sulfamylspiro [cyclohexane-l,2' (lH)-quinazolin] 4'(3'H)-one.

9. A compound according to claim 1 in which the compound is 7-chloro-1-methyl-6'-sulfamylspiro [piperidine- 4,2( 1H)-quinazolin] -4 (3 'H) -one.

10. A compound according to claim 1 in which the compound is 4,7-dichloro-6-sulfamylspiro [cyclohexane- 1,2(lH)-quinazolin]-4(3H)-one.

11. A compound according to claim 1 in which the compound is 7-chloro-2-mehty1-6'-sulfamylspiro [cyclohexane-1,2( l'H) -quinazolin]-4(3H)-one.

References Cited UNITED STATES PATENTS 3,452,019 6/1969 Shetty 260256.5

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl. XR. 

